Catalysis and asymmetric catalysis are processes of commercial importance in synthetic chemistry. The development of efficient methods to enable the reliable, stereocontrolled synthesis of small molecule target structures is an important goal relevant to the synthesis of compounds of commercial interest such as pharmaceutical drugs, agrochemicals and compounds with interesting materials properties. Asymmetric catalysis plays an important role in meeting this goal, and while tremendous advances have been realized in this rapidly moving field of research, significant problems remain. Among the most important of these problems are the need for (i) better substrate generality and/or more precisely substrate tunable catalyst systems, (ii) better catalyst stability (i.e., higher turnover number, TON), and (iii) better catalyst efficiency (i.e., higher turnover frequency, TOF). Solutions to these problems hinge on discovering and optimizing new ligands and catalyst systems, and understanding the reasons for their effectiveness. Most modular approaches start with one or a small set of scaffolds (equivalently, backbones or templates) and sequentially append the plural ligating substituents. The idea is to systematically vary the nature of the ligating groups (i.e., vary their elemental identity, shape, steric demand, and electronic character) to tune or optimize the asymmetric environment at the site of catalysis as well as define the nature of the metal-ligand interaction.
An interesting scaffold is selected and one sequentially couples a series of ligating substituents in ligand diversification steps. The ligands are then evaluated in the reaction(s) of interest. This linear synthetic approach employed with this strategy has worked well; however, the necessity for preparing as few as 20-25 chiral ligands using this approach greatly reduces the efficiency thereof. Limitations such as these demand new approaches to the problem.
For example, metal-directed self-assembly has been a very active area of research over the past decade and as a result facile routes to a wide variety of multiple metal containing metallocycles and metallocages have been defined [Holliday, B. J.; Mirkin, C. A “Strategies for the construction of supramolecular compounds through coordination chemistry,” Angew. Chem. Int. Ed. 2001, 40, 2022-2043; Leininger, S.; Olenyuk, B.; Stang, P. J. “Self-Assembly of Discrete Cyclic Nanostructures Mediated by Transition Metals,” Chem. Rev. 2000, 100,853-907]. The potential for novel uses of such structures has long been the goal of the research in this area, but to date, the preparation of functional structures is still rather rare [Yoshizawa, M.; Takeyama, Y.; Kusukawa, T.; Fujita, M. “Cavity-directed, highly stereoselective [2+2] photodimerization of olefins within self-assembled coordination cages,” Angew. Chem. Int. Ed. 2002,41,1347-1349]. Recently, several reports have appeared wherein self-assembly is used to generate novel bidentate ligands [Larsen, J.; Rasmussen, B. S.; Hazell, R. G.; Skrydstrup, T. “Preparation of a novel diphosphine-palladium macrocyclic complex possessing a molecular recognition site. Oxidative addition studies,” Chem. Commun. (Cambridge) 2004, 202-203; Braunstein, P.; Clerc, G.; Morise, X. “Cyclopropanation and Diels-Alder reactions catalyzed by the first heterobimetallic complexes with bridging phosphinooxazoline ligands,” New J. Chem. 2003, 27, 68-72; Braunstein, P.; Clerc, G.; Morise, X.; Welter, R.; Mantovani, G. “Phosphinooxazolines as assembling ligands in heterometallic complexes,” Dalton Transactions 2003, 1601-1605; Breit, B.; Seiche, W. “Hydrogen Bonding as a Construction Element for Bidentate Donor Ligands in Homogeneous Catalysis: Regioselective Hydroformylation of Terminal Alkenes,” J. Am. Chem. Soc. 2003, 125, 6608-6609; Siagt, V. F.; Van Leeuwen, P. W. N. M.; Reek, J. N. H. “Bidentate Ligands Formed by Self Assembly,” Chem. Commun. (Cambridge) 2003,2474-2475; Hua, J.; Un, W. “Chiral Metallacyclophanes: Self-Assembly, Characterization, and Application in Asymmetric Catalysis,” Org. Lett. 2004, 6, 861-864; Jiang, H.; Hu, A; Un, W. “A chiral metallacyclophane for asymmetric catalysis,” Chem. Commun. (Cambridge) 2003, 96-97; Lee, S. J.; Hu, A.; Un, W. “The First Chiral Organometallic Triangle for Asymmetric Catalysis,” J. Am. Chem. Soc. 2002, 124,12948-12949] and catalyst systems [Gianneschi, N. C.; Bertin, P. A.; Nguyen, S. T.; Mirkin, C. A; Zakharov, L. N.; Rheingold, A L. “A Supramolecular Approach to an Allosteric Catalyst,” J. Am. Chem. Soc. 2003, 125, 10508-10509; Mikami, K.; Tereda, M.; Korenaga, T.; Matsumoto, Y.; Ueki, M.; Angeluad, R. “Asymmetric activation,” Angew. Chem. Int. Ed. 2000, 39, 3532-3556; Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M. “Self-assembly of several components into a highly enantioselective Ti catalyst for carbonyl-ene reactions,” Angew. Chem., Int. Ed. Engl. 1998, 36, 2768-2771]. The general approach employed is outlined in FIG. 1. A metal-containing (or multiple metal-containing) scaffold is synthesized and combined with two or more bifunctional subunits leading to formation of the self-assembled ligand (SAL) 1. In general, the ligands prepared via this approach are symmetric since the ligating groups incorporated are identical; i.e., homoleptic complexes (i.e., two identical ligating groups) are formed. Several research-groups recently described successful efforts to prepare chiral SALs for asymmetric catalysis via the above described metal-directed self-assembly.
It is an object of the invention to provide novel asymmetric catalysts prepared by a novel combinatorial method.
It is a further object to provide novel catalyst systems containing the novel asymmetric catalysts.
It is a still further object of the invention to provide novel catalysis methods employing the novel asymmetric catalysts and catalyst systems of the invention.